Selenium (Se), an essential nutrient required for optimal growth of mammalian cells, affects the immune functions of a host in vivo. Utilizing a mouse model system and healthy human volunteers, we have shown that Se enhances the capacity of lymphocytes to respond to stimulation with mitogen or alloantigen, to proliferate, and to differentiate into cytotoxic effector cells. Supplementation with Se resulted in a significant increase in the tumor cytotoxicity of mouse cytotoxic lymphocytes, lymphokine activated killer cells and macrophages, and human cytotoxic lymphocytes and natural killer (NK) cells. Se also appears to abrogate the age-related deficiency of lymphocytes from an aged host to respond to stimulation by proliferation and differentiation into cytotoxic effector cells. These effects occurred in the absence of changes in the endogenous levels of interleukin-1, interleukin-2, or interferon-gamma, and were related to the ability of Se to enhance the expression of the alpha (p55) and/or beta (p70/75) subunits of the interleukin-2 receptor (IL-2R) on the surface of activated lymphocytes and NK cells. This resulted in a greater number of functional IL-2R/cell and in enhanced proliferation and clonal expansion of cytotoxic precursor cells. The molecular mechanism that mediates the effects of Se on immune cell function does not appear to be related to the function of Se as an antioxidant or to gene activation.